ABSTRACT The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) pandemic poses a major global health challenge. Coronavirus disease (COVID-19) is caused by SARS- CoV-2 and represents the causative agent of a potentially fatal disease. Science has moved very rapidly in isolating, sequencing, and cloning the virus, and developing diagnostic kits, within a matter of weeks. However, major knowledge gaps remain about the dynamic interaction between the human immune system and the SARS-CoV-2. In particular, several fundamental questions regarding its pathogenesis, and the mechanisms of protective immunity that need to be induced by vaccination, remain unanswered. Learning how the immune system senses SARS-CoV-2 infection and orchestrates protective immunity is critical for designing effective vaccines and therapeutics. Our previous work using systems biology, multi-omics approaches to analyze immune responses to vaccination in humans has delineated molecular signatures of innate immunity to vaccination and infection and have provided rich mechanistic insights into the immune response1-7. In this proposal, we propose a site-specific study to analyze samples from the IMPACC sub-study performed at Emory. We will use an integrated multi-omics approach (single cell transcriptomics, metabolomics, single cell epigenomics) to study innate immunity to COVID- 19 infection in humans. We will obtain PBMCs and tracheal aspirate samples from the IMPACC sub-study that will be conducted at Emory. We will address the following questions: What are the molecular and cellular signatures of the immune response to COVID-19 infection in the blood and tracheal aspirates of infected subjects? Does COVID-19 infection exert an epigenetic imprint of innate immunity? What is the molecular landscape and function of myeloid cell subsets and airway epithelial cells in the healthy lung, and following COVID-19 infection? These questions will be addressed in the following specific aims: 1) Determine the single cell transcriptional and epigenetic landscape of the immune response to COVID-19 infection in blood and tracheal aspirates, and 2) Determine the molecular identity and functions of myeloid cell subsets and epithelial cells in human lung and their response to COVID-19 infection. These studies will provide significant insight into the human immune response to COVID-19 infection that can be leveraged for designing vaccines and therapeutics to prevent or treat the infection.